PROCESS FOR THE PREPARATION OF AN ANTIPSYCHOTIC AGENT
Field of the Invention
A process for the preparation of an antipsychotic agent useful for the treatment of
schizophrenia is provided.
Background of the Invention
The present invention provides a process for the preparation of lurasidone
hydrochloride. Lurasidone hydrochloride is chemically (3aR,4S,7R,7aS)-2-{(lR,2R)-2-
[4-(l,2-benzisothiazol-3-yl)piperazin-l-ylmethyl]cyclohexylmethyl}hexahydro-4,7-
methano-2H-isoindole-l,3-dione hydrochloride having the structure as represented by
Formula I.
Formula I
Lurasidone hydrochloride is marketed in the United States under the brand name
Latuda® for the treatment of schizophrenia.
U.S. Patent No. 5,532,372 describes preparation of lurasidone hydrochloride using
racemic trans 1,2-cyclohexane dicarboxylic acid of Formula III as intermediate as
depicted in Scheme I.
Scheme I
Formula IX
The process described in U.S. Patent No. 5,532,372 involves use of racemic trans
1,2-cyclohexane dicarboxylic acid of Formula III as an intermediate. The trans
intermediate of Formula III may further exist as (R,R) trans and (S,S) trans isomers. In
the process described in U.S. Patent No. 5,532,372, resolution of free base of Formula IX
was carried out using a chiral resolving agent in the last step to obtain lurasidone followed
by subsequent conversion of lurasidone into lurasidone hydrochloride.
The present inventors have observed that chiral resolution of free base of an
intermediate of Formula IX is difficult due to the presence of six chiral centers. This
affects the overall yield and the cost of manufacturing. Thus, there exists a need for the
development of a simple, cost-effective, and industrially advantageous process for the
preparation of lurasidone hydrochloride which overcomes the difficulties of the prior art
process.
Summary of the Invention
The present invention provides an easy, cost-effective and industrially
advantageous process for the preparation of highly pure lurasidone hydrochloride which
involves separating the racemic trans 1, 2-cyclohexane dicarboxylic acid of Formula III
into its R,R trans and S,S trans isomers and then using the desired trans R,R isomer for
the preparation of lurasidone hydrochloride. Since the process of the present invention
involves separating the undesired S,S trans isomer in the initial stages of the
manufacturing process, no undesired isomers due to reaction with trans (S,S)-isomer are
formed in the subsequent steps.
Lurasidone hydrochloride prepared by the process of the present invention is a
highly pure, easy to filter, free-flowing solid having small average particle size.
A first aspect of the present invention provides a process for the preparation of
lurasidone hydrochloride of Formula I
Formula I
comprising the steps of:
i) Resolving trans (racemic)-!, 2-cyclohexane dicarboxylic acid of Formula III
Formula III
trans (racemic)
into trans (R,R)-l,2-cyclohexane dicarboxylic acid of Formula Ilia
Formula Ilia
trans (R,R)-isomer
Converting trans (R,R)-l,2-cyclohexane dicarboxylic acid of Formula Ilia
into trans (R,R)-dicarboxylate intermediate of Formula X, wherein R is Ci
C alkyl or benzyl;
Formula X
frans(R,R)-isomer
Converting trans (R,R)-dicarboxylate intermediate of Formula X into trans
(R,R)-l,2-bis(hydroxymethyl)cyclohexane of Formula XI;
Formula XI
7 (R,R)-isome r
iv) Converting trans (R,R)- 1,2-bis(hydroxymethyl)cyclohexane of Formula XI
into an intermediate of Formula XII
Formula XII
fraAjs(R,R)-isomer
wherein R' is a leaving group;
Reacting intermediate of Formula XII with 3-(l-piperazinyl-l,2-
benzisothiazole) of Formula VI
Formula VI
to obtain trans (R,R)-3a,7a-octahydroisoindolium-2-spiro- -[4'-(l,2-
benzoisothiazole-3-yl)]piperazine methane sulfonate of Formula Vila;
Formula Vila
irans(R,R)-isomer
Reacting trans (R,R)-3a,7a-octahydroisoindolium-2-spiro-l'-[4'-(l,2-
benzoisothiazole-3-yl)]piperazine methane sulfonate of Formula Vila with
bicyclo[2.2. l]heptane-2-exo-3-exo-dicarboximide intermediate of Formula
VIII
Formula VIII
to obtain lurasidone of Formula CPI; and
Formula XIII
vii) Treating lurasidone of Formula XIII with hydrogen chloride to obtain
lurasidone hydrochloride of Formula I.
A second aspect of the present invention provides use of trans (R,R)-1,2-
cyclohexane dicarboxylic acid of Formula Ilia
Formula Ilia
trans (R,R)-isomer
for the preparation of lurasidone hydrochloride of Formula I.
Detailed Description of the Invention
Various embodiments and variants of the present invention are described
hereinafter.
The term "ambient temperature", as used herein, refers to a temperature in the
range of about 20°C to about 35°C.
The term "contacting", as used herein, refers to dissolving, slurrying, stirring or a
combination thereof.
Racemic trans 1,2-cyclohexane dicarboxylic acid of Formula III, to be used for the
preparation of lurasidone hydrochloride of Formula I of the present invention, may be
obtained by methods known in the literature such as the one disclosed in U.S. Patent No.
5,532,372, which is incorporated herein by reference. It may be obtained as a solution
directly from a reaction in which it is formed and used as such without isolation or it may
be isolated and then used in the next step.
Racemic trans 1,2-cyclohexane dicarboxylic acid of Formula III may be resolved
into (R,R) trans 1,2-cyclohexane dicarboxylic acid of Formula Ilia and (S,S) trans 1,2-
cyclohexane dicarboxylic acid using a chiral resolving agent selected from the group
comprising (R)-l-phenylethyl amine, alpha-methylbenzylamine, l-(l-naphthyl)-
ethylamine, sec-butylamine l-amino-2-methylbutane, N,N-dimethyl-l-phenylethylamine,
1-cyclohexylethylamine, 2-(methoxymethyl)-pyrrolidine, l-(4-nitrophenyl)-ethylamine, 2-
amino-l-butanol, l-amino-2-propanol, cinchonidine, brucine, strychnine, cinchonine, Nmethyl-
ephedrine or alpha-phenyl-glycinol. In a preferred embodiment, the resolving
agent used is (R)-l-phenylethyl amine.
Resolution may be carried out using a solvent selected from the group comprising
alcohols, ketones, alkyl acetates, chlorinated hydrocarbons, ethers, nitriles or
hydrocarbons. Examples of alcohols are methanol, ethanol, n-propanol, iso-propanol, nbutanol,
iso-butanol, sec-butanol or n-pentanol. Examples of ketones are acetone, methyl
ethyl ketone or methyl isobutyl ketone. Examples of alkyl acetates are ethyl acetate or
isopropyl acetate. Examples of chlorinated hydrocarbons are dichloromethane or
chloroform. Examples of ethers are diethyl ether, diisopropyl ether, methyl butyl ether,
tetrahydrofiiran or dioxane. Examples of nitriles are acetonitrile or propionitrile.
Examples of hydrocarbons are benzene, xylene, toluene, hexanes, heptane or pentane.
Resolving agent may be added at a temperature of about 0°C to -100°C. The
reaction mixture may be stirred for about 30 minutes to about 2 hours, warmed to ambient
temperature and stirred for about 2 hours to about 10 hours followed by isolation.
Isolation may be accomplished by filtration and drying. Drying may be carried out
using any suitable method such as drying under reduced pressure, drying under
atmospheric pressure, air drying or drying with aeration of inert gas such as nitrogen.
Drying may be carried out at a temperature of about 40°C to about 80°C for about 2 hours
to about 10 hours.
The salt of trans 1,2-cyclohexane dicarboxylic acid of Formula III with the
resolving agent may be further purified by crystallization from the solvent selected from
the group consisting of alcohols, hydrocarbons, ketones, alkyl acetates, chlorinated
hydrocarbons, ethers, nitriles and mixtures thereof. Examples of alcohols are methanol,
ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, sec-butanol, and n-pentanol.
Examples of hydrocarbons are benzene, xylene, toluene, hexane, heptanes, and pentane.
Examples of ketones are acetone, methyl ethyl ketone, and methyl isobutyl ketone.
Examples of alkyl acetates are ethyl acetate, and isopropyl acetate. Examples of
chlorinated hydrocarbons are dichloromethane and chloroform. Examples of ethers are
diethyl ether, diisopropyl ether, methyl butyl ether, tetrahydrofuran, and dioxane.
Examples of nitriles are acetonitrile and propionitrile. In a preferred embodiment, salt of
(R,R) trans 1,2-cyclohexane dicarboxylic acid of Formula Ilia with the resolving agent is
purified by crystallization from a solvent mixture comprising an alcohol and a
hydrocarbon.
Crystallization may be carried out by dissolving the salt of trans 1,2-cyclohexane
dicarboxylic acid of Formula III with the resolving agent at a temperature of about 60°C to
about 100°C. The solution may be cooled to about -10°C to an ambient temperature,
stirred for about 30 minutes to about 2 hours, filtered and dried. The crystallization step
may be repeated if required. The solid material thus obtained may be dissolved in about
IN hydrochloric acid solution, extracted with a solvent and isolated to obtain trans (R,R)-
1,2-cyclohexane dicarboxylic acid of Formula Ilia. In a preferred embodiment,
purification is carried out by crystallization from ethanohtoluene mixture. In another
preferred embodiment, purification is carried out by crystallization from ethanohtoluene
mixture (1:1) mixture.
Conversion of (R,R) trans 1,2-cyclohexane dicarboxylic acid of Formula Ilia into
dicarboxylate intermediate of Formula X may be carried out by contacting with a Ci-C4
alcohol or benzyl alcohol in the presence of sulphuric acid. Examples of C1-C4 alcohols
are methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, and sec-butanol.
The reaction mixture may be stirred at about 25°C to 60°C for about 1 hour to 24 hours
and concentrated. Isolation may be accomplished by adding de-ionized water, solvent
extraction and concentration.
In a particular embodiment, trans (R,R)-l,2-cyclohexane dicarboxylic acid of
Formula Ilia may be converted into trans (R,R)-l,2-dimethyl cyclohexane dicarboxylate
of Formula X by contacting with methanol in the presence of sulphuric acid. The reaction
mixture may be stirred at about 40°C for about 18 hours. The reaction mixture may be
concentrated under reduced pressure at about 50°C. De-ionized water may be added.
Isolation of trans (R,R)-l,2-dimethyl cyclohexane dicarboxylate may be accomplished by
solvent extraction and concentration.
Conversion of dicarboxylate intermediate of Formula X into trans (R,R)-1,2-
bis(hydroxymethyl)cyclohexane of Formula XI may be carried out by adding a reducing
agent selected from the group comprising diisobutyl aluminum hydride, lithium
aluminium hydride, lithium borohydride, sodium borohydride, calcium borohydride, and
lithium triethylborohydride, in an inert atmosphere. A solvent selected from the group
comprising hydrocarbons or ethers may be added. Examples of hydrocarbons are
benzene, xylene, toluene, hexane, heptanes or pentane. Examples of ethers are diethyl
ether, diisopropyl ether, methyl butyl ether, tetrahydrofuran, diglyme or dioxane. The
reducing agent may be added drop-wise at a temperature of about -10°C to 10°C. The
reaction mixture may be warmed to an ambient temperature and stirred for about 2 hours
to 10 hours. About IN hydrochloric acid solution may be added at about -5°C to 40°C.
The reaction mixture may be stirred for about 10 hours to 15 hours. Isolation may be
accomplished by filtration and concentration.
In a preferred embodiment, conversion of dicarboxylate intermediate of Formula X
into trans (R,R)-l,2-bis(hydroxymethyl)cyclohexane of Formula XI may be carried out
using diisobutyl aluminum hydride in a hydrocarbon solvent. In a more preferred
embodiment, conversion of dicarboxylate intermediate of Formula X into trans (R,R)-1,2-
bis(hydroxymethyl)cyclohexane of Formula XI may be carried out using diisobutyl
aluminum hydride in toluene.
The hydroxyl group of trans (R,R)-l,2-bis(hydroxymethyl)cyclohexane of
Formula XI may be converted into a leaving group by reaction with a halide or a
sulphonyl compound to obtain a intermediate of Formula XII. Examples of halides are
thionyl chloride and thionyl bromide. Examples of sulphonyl compounds are alkyl- or
aryl-sulphonyl halides selected from the group comprising of methane sulphonyl chloride,
ethane sulphonyl chloride, p-toluene sulphonyl chloride, and benzene sulphonyl chloride.
An organic or inorganic base may be added. Examples of organic bases are triethylamine,
ammonia, and pyridine. Examples of inorganic bases are hydroxides, carbonates and
bicarbonates of alkali and alkaline earth metals such as sodium carbonate, potassium
carbonate, sodium bicarbonate, lithium hydroxide, sodium hydroxide, and potassium
hydroxide. Conversion may be carried out in the presence of a solvent selected from the
group comprising of chlorinated hydrocarbons such as dichloromethane or chloroform or
in pyridine at a temperature of about -10°C to about 10°C. The reaction mixture may be
further stirred at ambient temperature for about 1 hour to 8 hours. De-ionized water may
be added. Organic layer may be concentrated at a temperature of about 35°C to 60°C.
Precipitation of the hydroxyl protected intermediate may be achieved by adding an ether
solvent such as diethyl ether, diisopropyl ether, methyl butyl ether, tetrahydrofuran,
diglyme or dioxane, stirring for about 30 minutes to 2 hours followed by isolation.
In a preferred embodiment, trans (R,R)-l,2-iw(hydroxymethyl)cyclohexane may
be converted into trans (R,R)-l,2-Z>w(methanesulfonylmethyl)cyclohexane using methane
sulphonyl chloride in the presence of triethylamine. Addition of methane sulphonyl
chloride may be carried out at a temperature of about -10°C to 10°C in a chlorinated
solvent. Reaction mixture may be stirred at ambient temperature for about 1 hour to 8
hours. De-ionized water may be added. Organic layer may be concentrated at about 45°C
under reduced pressure. Precipitation of trans (R, R)-l,2-
Z>/s(methanesulfonylmethyl)cyclohexane may be achieved using di-isopropyl ether. The
reaction mixture may be stirred at an ambient temperature for about 30 minutes to 2 hours
followed by isolation.
trans (R,R)-l,2-bis(methanesulfonylmethyl)cyclohexane may be converted to
trans (R,R)-3a,7a-octahydroisoindolium-2-spiro-l'-[4'-(l,2-benzoisothiazole-3-
yl)]piperazine methane sulfonate of Formula Vila by contacting with 3-(l-piperazinyl-l,2-
benzisothiazole) of Formula VI in a nitrile or amide solvent in the presence of a base.
Examples of nitriles are acetonitrile and propionitrile. Examples of amide solvents are
N,N-dimethyl formamide and N,N-diethylformamide. Examples of bases are carbonates,
bicarbonates and hydroxides of alkali and alkaline earth metals such as sodium carbonate,
potassium carbonate, sodium bicarbonate, lithium hydroxide, sodium hydroxide, and
potassium hydroxide. The reaction mixture may be refluxed for about 1 hours to 2 days,
filtered and concentrated at about 40°C to 80°C under reduced pressure. Precipitation may
be achieved by adding a ketone solvent, a hydrocarbon solvent or mixtures thereof.
Examples of ketones are acetone, methyl ethyl ketone, and methyl isobutyl ketone.
Examples of hydrocarbons are benzene, xylene, toluene, hexane, heptanes, and pentane.
The reaction mixture may be stirred for about 10 minutes to 1 hour followed by isolation.
trans (R,R)-3a,7a-octahydroisoindolium-2-spiro-r-[4'-(l,2-benzoisothiazole-3-
yl)]piperazine methane sulfonate of Formula Vila may be reacted with
bicyclo[2.2.1]heptane-2-exo-3-exo-dicarboximide of Formula VIII in the presence of a
catalyst and a base. The catalyst may be selected from crown ethers such as dibenzo-18-
crown-6 or 18-crown-6. Examples of bases are carbonates, bicarbonates and hydroxides
of alkali and alkaline earth metals such as sodium carbonate, potassium carbonate, sodium
bicarbonate, lithium hydroxide, sodium hydroxide, and potassium hydroxide. Hydrides of
alkali metals such as sodium hydride and potassium hydride may also act as base. The
reaction may be carried out in a hydrocarbon solvent selected from the group comprising
benzene, xylene, toluene, hexane, heptanes, and pentane. The reaction mixture may be
refluxed for about 1 hour to 2 days, filtered and concentrated at about 40°C to 100°C
under reduced pressure. Precipitation of lurasidone may be carried out by adding an
alcohol selected from methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol,
sec-butanol or n-pentanol followed by isolation.
Lurasidone may be converted into lurasidone hydrochloride by drop-wise addition
of hydrogen chloride to a solution of lurasidone in a solvent. The solvent may be selected
from the group comprising alcohols, alkyl acetates, ketones, and hydrocarbons. Examples
of alcohols are methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, secbutanol,
and n-pentanol. Examples of alkyl acetates are ethyl acetate and isopropyl
acetate. Examples of ketones are acetone, methyl ethyl ketone, and methyl isobutyl
ketone. Examples of hydrocarbons are benzene, xylene, toluene, hexane, heptanes, and
pentane. Conversion of lurasidone into lurasidone hydrochloride may be carried out by
purging hydrogen chloride gas or by adding aqueous hydrochloric acid in a solvent
selected from iso-propanol, ethyl acetate, toluene, and water at ambient temperature to
about 80°C. The reaction mixture may be stirred at ambient temperature to the reflux
temperature of the solvent for about 10 minutes to 1 hour followed by isolation.
When aqueous hydrogen chloride is used for the conversion of lurasidone into
lurasidone hydrochloride, the concentration of aqueous hydrogen chloride may vary from
0.1% to 36%.
In a preferred embodiment, lurasidone may be converted to lurasidone
hydrochloride by contacting a solution of lurasidone in ethyl acetate with 6% to 8%
aqueous hydrogen chloride at about 40°C, stirring at ambient temperature for about 30
minutes to 5 hours followed by isolation.
Lurasidone hydrochloride prepared by the process of the present invention is a
highly pure, easy to filter, free-flowing solid having small average particle size.
In the foregoing section, embodiments are described by way of examples to
illustrate the processes of invention. However, these are not intended in any way to limit
the scope of the present invention. Several variants of the examples would be evident to
persons ordinarily skilled in the art which are within the scope of the present invention.
Methods
HPLC purity was determined using Water alliances, Model 2695 instrument.
EXAMPLES
Example 1: Preparation of trans fR..RH.2-Cyclohexane Dicarboxylic Acid
To a suspension of racemic trans 1,2-cyclohexane dicarboxylic acid (65 g) in
ethanol (650 mL) was added (R)-l-phenylethyl amine (50.7 mL) at about -70°C. The
reaction mixture was stirred for about 90 minutes, warmed to ambient temperature and
stirred for about 5 hours. Precipitates were filtered, washed with ethanol (25 mL) and
dried under reduced pressure at about 40°C to obtain crude salt of trans (R,R)- 1,2-
cyclohexane dicarboxylic acid (96.5 g).
The salt of trans (R,R)-l,2-cyclohexane dicarboxylic acid, obtained above, was
dissolved in ethanol:toluene (1:1) mixture (1.4 L) at about 80°C. The solution was cooled
to about 0°C to about 5°C over a period of about 60 minutes to about 90 minutes, filtered
and dried under reduced pressure at about 45°C. Crystallization was repeated twice. Solid
material, thus obtained, was dissolved in about IN hydrogen chloride (250 mL) and
extracted two times with ethyl acetate (600+300 mL). Organic layers were combined,
washed with brine and concentrated at about 45°C under reduced pressure to obtain trans
(R,R)-l,2-cyclohexane dicarboxylic acid as colorless crystals.
Yield: 30%
Example 2: Preparation of trans (R,RV1.2-Dimethyl Cyclohexane Dicarboxylate
Sulphuric acid (9 mL) was added to a solution of trans (R,R)-l,2-cyclohexane
dicarboxylic acid (18 g) in methanol (180 mL). The reaction mixture was stirred at about
40°C for about 18 hours. The reaction mixture was concentrated at about 50°C under
reduced pressure. De-ionized water (150 mL) was added. The reaction mixture was
extracted twice with ethyl acetate (150 + 100 mL). The organic layers were combined,
washed with brine and concentrated under reduced pressure at about 50°C to obtain trans
(R,R)-l,2-dimethyl cyclohexane dicarboxylate as an oil.
Yield: 97%
Example 3: Preparation of trans (Tl.RV1.2-Bis(HvdroxymethvDCyclohexane
trans (R,R)-l,2-dimethyl cyclohexane dicarboxylate (20 g) was dissolved in
toluene (200 mL) at about 0°C to about -5°C in an inert atmosphere. Diisobutyl aluminum
hydride (248.5 ml, 20% solution in toluene) was added drop-wise into the above solution.
The reaction mixture was warmed to an ambient temperature and stirred for about 6 hours.
The reaction was quenched by drop-wise addition of about IN HC1 (125 mL) at about
-5°C to about 40°C. The reaction mixture was further stirred for about 13 hours to get
freely filterable inorganic solids. The solids were filtered out and the filtrate was
concentrated under reduced pressure to obtain trans (R,R)-1,2-
bis(hydroxymethyl)cyclohexane as an oil.
Yield: 74%
Example 4: Preparation of trans (R,RH.2-Z?/s(MethanesulfonylmethvDCyclohexane
Methane sulfonyl chloride (23.85 g) was added to a solution of (R,R) trans 1,2-
£/s(hydroxymethyl)cyclohexane (10.0 g) and triethylamine (15.45 g) in chloroform (100
mL) at about 0°C to about 5°C. The reaction mixture was stirred at an ambient
temperature for about 5 hours. De-ionized water (120 mL) was added. The organic layer
was separated and concentrated under reduced pressure at about 45°C. Diisopropyl ether
(120 mL) was added. The reaction mixture was stirred at ambient temperature for about
60 minutes, filtered and dried under reduced pressure at about 40°C to obtain trans (R,R)-
l,2-bis(methanesulfonylmethyl)cyclohexane.
Yield: 90.8%
Example 5: Preparation of trans (R Rl-SaJa-Octahydroisoindolium^-Spiro - - ' - -
Benzoisothiazole-3-YD]Piperazine Methane Sulfonate
3-(l-Piperazinyl-l,2-benzisothiazole) (13.2 g) and sodium carbonate (6.5 g) were
added to a solution of trans (R,R)-l,2-bis(methanesulfonylmethyl)cyclohexane (18 g) in
acetonitrile (180 mL) at ambient temperature. The reaction mixture was refluxed for
about 30 hours, filtered and washed with acetonitrile (2x25 mL). The combined filtrate
was concentrated at about 60°C under reduced pressure. Acetone (40 mL) was added to
the residue and the reaction mixture was stirred at about 40°C until the product
precipitated out. Hexane (50 mL) was added. The reaction mixture was stirred for about
30 minutes at ambient temperature, filtered and dried under reduced pressure at about
45°C for about 8 hours to obtain trans (R,R)-3a,7a-octahydroisoindolium-2-spiro-l'-[4'-
(l,2-benzoisothiazole-3-yl)]piperazine methane sulfonate.
Yield: 88%
Example 6: Preparation of Lurasidone
Method A:
Bicyclo[2.2.1]heptane-2-exo-3-exo-dicarboximide (7.5 g), potassium carbonate
(7.5 g) and dibenzo-18-crown-6 (0.15 g) were added to a solution of trans (R,R)-3a,7aoctahydroisoindolium-
2-spiro - -[4'-(l,2-benzoisothiazole-3-yl)]piperazine methane
sulfonate (15 g) in xylene (150 mL). The reaction mixture was refluxed for about 25
hours, filtered and concentrated at about 70°C under reduced pressure. Sticky residue was
obtained. Isopropanol (30 mL) was added. The reaction mixture was cooled to ambient
temperature, stirred for about 5 hours, filtered, washed with isopropanol (15 mL) and dried
at about 45°C under reduced pressure for about 15 hours to obtain lurasidone.
Yield: 76.8%
Method B :
Bicyclo[2.2.1]heptane-2-exo-3-exo-dicarboximide (7.5 g), potassium carbonate
(7.5 g) and dibenzo-18-crown-6 (0.15 g) were added to a solution of trans (R,R)-3a,7aoctahydroisoindolium-
2-spiro - -[4'-(l,2-benzoisothiazole-3-yl)]piperazine methane
sulfonate (15 g) in toluene (150 mL). The reaction mixture was refluxed for about 12
hours, filtered and concentrated at about 55°C to 60°C under reduced pressure. Sticky
residue was obtained. Denatured spirit (75 mL) was added. The reaction mixture was
heated to about 40°C, maintained for about 1 hour, cooled to ambient temperature and
stirred for about 6 hours. The solid was filtered, washed with denatured spirit (20 mL) and
dried at about 45°C under reduced pressure for about 15 hours to obtain lurasidone free
base.
Yield: 86.35%
HPLC Purity: 98.41%
Example 7: Preparation of Lurasidone Hydrochloride
About 7% aqueous hydrochloric acid (5 mL) was slowly added to a reaction
mixture containing lurasidone (1.0 g) in ethyl acetate (25 mL) at about 40°C. The reaction
mixture was stirred at ambient temperature for about 2 hours, filtered and dried at about
45°C under reduced pressure to obtain lurasidone hydrochloride.
Yield: 93%
HPLC Purity: 98.98%
We Claim:
1. A process for the preparation of lurasidone hydrochloride of Formula I
Formula I
comprising the steps of:
i) Resolving trans (racemic)-l,2-cyclohexane dicarboxylic acid of Formula III
Formula III
trans (racemic)
into trans (R,R)-l,2-cyclohexane dicarboxylic acid of Formula Ilia;
COOH
COOH
Formula Ilia
trans (R,R)-isomer
Converting trans (R,R)-l,2-cyclohexane dicarboxylic acid of Formula Ilia
into trans (R,R)-dicarboxylate intermediate of Formula X, wherein R is C
C alkyl or benzyl;
Formula X
trans(R, R)-isomer
iii) Converting trans (R,R)-dicarboxylate intermediate of Formula X into trans
(R,R)-l,2-bis(hydroxymethyl)cyclohexane of Formula XI;
Formula XI
fra/7s(R,R)-isomer
Converting trans (R,R)-l,2-bis(hydroxymethyl)cyclohexane of Formula XI
into an intermediate of Formula XII
Formula XII
f/a/7s(R,R)-isomer
wherein R' is a leaving group;
v) Reacting intermediate of Formula XII with 3-(1-piperazinyl- 1,2-
benzisothiazole) of Formula VI
Formula VI
to obtain trans (R,R)-3a,7a-octahydroisoindolium-2-spiro-l'-[4'-(l,2-
benzoisothiazole-3-yl)]piperazine methane sulfonate of Formula Vila;
Formula Vila
trans(R, R)-isomer
Reacting trans (R, R)-3a,7a-octahydroisoindolium-2-spiro -r-[4'-(l,2-
benzoisothiazole-3-yl)]piperazine methane sulfonate of Formula Vila with
bicyclo[2.2. l]heptane-2-exo-3-exo-dicarboximide intermediate of Formula
VIII
Formula VIII
to obtain lurasidone of Formula XIII; and
Formula XIII
vii) Treating lurasidone of Formula XIII with hydrogen chloride to obtain
lurasidone hydrochloride of Formula I.
2. The process according to claim 1, wherein resolution is carried out using a chiral
resolving agent.
3. The process according to claim 1, wherein the resolution is carried out at a
temperature of about 0°C to -100°C.
4. The process according to claim 1, wherein the salt of trans 1,2-cyclohexane
dicarboxylic acid of Formula III with the resolving agent is further purified by
crystallization from a solvent selected from alcohols, hydrocarbons, ketones, alkyl
acetates, chlorinated hydrocarbons, ethers, nitriles, or mixtures thereof.
5. The process according to claim 1, wherein conversion of trans (R,R)-1 ,2-
cyclohexane dicarboxylic acid of Formula Ilia into trans (R,R)-dicarboxylate intermediate
of Formula X is carried out in a C1-C4 alcohol or benzyl alcohol.
6. The process according to claim 1, wherein conversion of trans (R,R)- 1,2-
cyclohexane dicarboxylic acid of Formula Ilia into trans (R,R)-dicarboxylate intermediate
of Formula X is carried out at about 40°C.
7. The process according to claim 1, wherein conversion of trans (R,R)-dicarboxylate
intermediate of Formula X into trans (R,R)-l,2-bis(hydroxymethyl)cyclohexane of
Formula XI is carried out by adding a reducing agent in a hydrocarbon or ether solvent.
8. The process according to claim 1, wherein conversion of trans (R,R)-1,2-
bis(hydroxymethyl)cyclohexane of Formula XI into trans R,R intermediate of Formula
XII by reaction with a halide or sulphonyl compound in the presence of a base in a
chlorinated hydrocarbon or pyridine.
9. The process according to claim 1, wherein trans R,R intermediate of Formula XII
is reacted with 3-(l-piperazinyl-l,2-benzisothiazole) of Formula VI in the presence of a
base in a nitrile or amide solvent to obtain trans (R,R)-3a,7a-octahydroisoindolium-2-
spiro-l'-[4'-(l,2-benzoisothiazole-3-yl)]piperazine methane sulfonate of Formula Vila.
10. The process according to claim 1, wherein the reaction of trans (R,R)-3a,7aoctahydroisoindolium-
2-spiro-l'-[4'-(l,2-benzoisothiazole-3-yl)]piperazine methane
sulfonate of Formula Vila with bicyclo[2.2.1]heptane-2-exo-3-exo-dicarboximide
intermediate of Formula VIII is carried out in the presence of a base in a hydrocarbon
solvent.
11. The process according to claim 1, wherein a solution of lurasidone in ethyl acetate
is treated with 7% aqueous hydrochloric acid.
12. Use of trans (R,R)-l,2-cyclohexane dicarboxylic acid of Formula Ilia
Formula Ilia
trans (R,R)-isomer
for the preparation of lurasidone hydrochloride.